An Agrin–YAP/TAZ Rigidity Sensing Module Drives EGFR-Addicted Lung Tumorigenesis

Reza Bayat Mokhtari; Divyaleka Sampath; Paige Eversole; Melissa Ong Yu Lin; Dmitriy A. Bosykh; Gandhi T.K. Boopathy; Aravind Sivakumar; Cheng Chun Wang; Ramesh Kumar; Joe Yeong Poh Sheng; Ellen Karasik; Barbara A. Foster; Han Yu; Xiang Ling; Wenjie Wu; Fengzhi Li; Zoë Weaver Ohler; Christine F. Brainson; David W. Goodrich; Wanjin Hong; Sayan Chakraborty

doi:10.1002/advs.202413443

An Agrin–YAP/TAZ Rigidity Sensing Module Drives EGFR-Addicted Lung Tumorigenesis

Reza Bayat Mokhtari, Divyaleka Sampath, Paige Eversole, Melissa Ong Yu Lin, Dmitriy A. Bosykh, Gandhi T.K. Boopathy, Aravind Sivakumar, Cheng Chun Wang, Ramesh Kumar, Joe Yeong Poh Sheng, Ellen Karasik, Barbara A. Foster, Han Yu, Xiang Ling, Wenjie Wu, Fengzhi Li, Zoë Weaver Ohler, Christine F. Brainson, David W. Goodrich, Wanjin HongSayan Chakraborty

Research output: Contribution to journal › Article › peer-review

Abstract

Despite epidermal growth factor receptor (EGFR) is a pivotal oncogene for several cancers, including lung adenocarcinoma (LUAD), how it senses extracellular matrix (ECM) rigidity remain elusive in the context of the increasing role of tissue rigidity on various hallmarks of cancer development. Here it is shown that EGFR dictates tumorigenic agrin expression in lung cancer cell lines, genetically engineered EGFR-driven mouse models, and human specimens. Agrin expression confers substrate stiffness-dependent oncogenic attributes to EGFR-reliant cancer cells. Mechanistically, agrin mechanoactivates EGFR through epidermal growth factor (EGF)-dependent and independent modes, thereby sensitizing its activity toward localized cancer cell-ECM adherence and bulk rigidity by fostering interactions with integrin β1. Notably, a feed-forward loop linking agrin–EGFR rigidity response to YAP–TEAD mechanosensing is essential for tumorigenesis. Together, the combined inhibition of EGFR–YAP/TEAD may offer a strategy to reduce lung tumorigenesis by disrupting agrin-EGFR mechanotransduction, uncovering a therapeutic vulnerability for EGFR-addicted lung cancers.

Original language	English
Article number	2413443
Journal	Advanced Science
Volume	12
Issue number	20
DOIs	https://doi.org/10.1002/advs.202413443
State	Published - May 29 2025

Bibliographical note

Publisher Copyright:
© 2025 The Author(s). Advanced Science published by Wiley-VCH GmbH.

Funding

The authors thank Dr Wiam Bshara and Leighton Stein from the pathology shared network resources at Roswell Park for immunohistochemistry (IHC) studies. The authors are also grateful to Dr. Deanna Conners for critically reading the manuscript. All cartoons and schematics were prepared using Biorender. This study was funded in\u2010part from core start\u2010up funds and Developmental Therapeutics Grant to S.C, from the Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, and core funds from IMCB to W.H., and R01CA237643 and Biospecimen Procurement and Translational Pathology Shared Resource Facilities P30CA177558 to C.F.B. Editorial assistance for this publication was provided by Roswell Park's Scientific Editing and Research Communications Core (SERCC) Resource, which is supported by a National Cancer Institute (NCI) Cancer Center Support Grant (NCI P30CA016056).

Funders	Funder number
Department of Pharmacology and Experimental Therapeutics
SERCC
International Institute of Molecular and Cell Biology	P30CA177558, R01CA237643
International Institute of Molecular and Cell Biology
National Childhood Cancer Registry – National Cancer Institute	P30CA016056
National Childhood Cancer Registry – National Cancer Institute

Keywords

EGFR, extracellular matrix
YAP/TAZ
agrin
hippo pathway
lung cancer

ASJC Scopus subject areas

Medicine (miscellaneous)
General Chemical Engineering
General Materials Science
Biochemistry, Genetics and Molecular Biology (miscellaneous)
General Engineering
General Physics and Astronomy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/advs.202413443

Cite this

Mokhtari, R. B., Sampath, D., Eversole, P., Yu Lin, M. O., Bosykh, D. A., Boopathy, G. T. K., Sivakumar, A., Wang, C. C., Kumar, R., Sheng, J. Y. P., Karasik, E., Foster, B. A., Yu, H., Ling, X., Wu, W., Li, F., Ohler, Z. W., Brainson, C. F., Goodrich, D. W., ... Chakraborty, S. (2025). An Agrin–YAP/TAZ Rigidity Sensing Module Drives EGFR-Addicted Lung Tumorigenesis. Advanced Science, 12(20), Article 2413443. https://doi.org/10.1002/advs.202413443

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title = "An Agrin–YAP/TAZ Rigidity Sensing Module Drives EGFR-Addicted Lung Tumorigenesis",

abstract = "Despite epidermal growth factor receptor (EGFR) is a pivotal oncogene for several cancers, including lung adenocarcinoma (LUAD), how it senses extracellular matrix (ECM) rigidity remain elusive in the context of the increasing role of tissue rigidity on various hallmarks of cancer development. Here it is shown that EGFR dictates tumorigenic agrin expression in lung cancer cell lines, genetically engineered EGFR-driven mouse models, and human specimens. Agrin expression confers substrate stiffness-dependent oncogenic attributes to EGFR-reliant cancer cells. Mechanistically, agrin mechanoactivates EGFR through epidermal growth factor (EGF)-dependent and independent modes, thereby sensitizing its activity toward localized cancer cell-ECM adherence and bulk rigidity by fostering interactions with integrin β1. Notably, a feed-forward loop linking agrin–EGFR rigidity response to YAP–TEAD mechanosensing is essential for tumorigenesis. Together, the combined inhibition of EGFR–YAP/TEAD may offer a strategy to reduce lung tumorigenesis by disrupting agrin-EGFR mechanotransduction, uncovering a therapeutic vulnerability for EGFR-addicted lung cancers.",

keywords = "EGFR, extracellular matrix, YAP/TAZ, agrin, hippo pathway, lung cancer",

author = "Mokhtari, \{Reza Bayat\} and Divyaleka Sampath and Paige Eversole and \{Yu Lin\}, \{Melissa Ong\} and Bosykh, \{Dmitriy A.\} and Boopathy, \{Gandhi T.K.\} and Aravind Sivakumar and Wang, \{Cheng Chun\} and Ramesh Kumar and Sheng, \{Joe Yeong Poh\} and Ellen Karasik and Foster, \{Barbara A.\} and Han Yu and Xiang Ling and Wenjie Wu and Fengzhi Li and Ohler, \{Zo{\"e} Weaver\} and Brainson, \{Christine F.\} and Goodrich, \{David W.\} and Wanjin Hong and Sayan Chakraborty",

note = "Publisher Copyright: {\textcopyright} 2025 The Author(s). Advanced Science published by Wiley-VCH GmbH.",

year = "2025",

month = may,

day = "29",

doi = "10.1002/advs.202413443",

language = "English",

volume = "12",

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Mokhtari, RB, Sampath, D, Eversole, P, Yu Lin, MO, Bosykh, DA, Boopathy, GTK, Sivakumar, A, Wang, CC, Kumar, R, Sheng, JYP, Karasik, E, Foster, BA, Yu, H, Ling, X, Wu, W, Li, F, Ohler, ZW, Brainson, CF, Goodrich, DW, Hong, W & Chakraborty, S 2025, 'An Agrin–YAP/TAZ Rigidity Sensing Module Drives EGFR-Addicted Lung Tumorigenesis', Advanced Science, vol. 12, no. 20, 2413443. https://doi.org/10.1002/advs.202413443

TY - JOUR

T1 - An Agrin–YAP/TAZ Rigidity Sensing Module Drives EGFR-Addicted Lung Tumorigenesis

AU - Mokhtari, Reza Bayat

AU - Sampath, Divyaleka

AU - Eversole, Paige

AU - Yu Lin, Melissa Ong

AU - Bosykh, Dmitriy A.

AU - Boopathy, Gandhi T.K.

AU - Sivakumar, Aravind

AU - Wang, Cheng Chun

AU - Kumar, Ramesh

AU - Sheng, Joe Yeong Poh

AU - Karasik, Ellen

AU - Foster, Barbara A.

AU - Yu, Han

AU - Ling, Xiang

AU - Wu, Wenjie

AU - Li, Fengzhi

AU - Ohler, Zoë Weaver

AU - Brainson, Christine F.

AU - Goodrich, David W.

AU - Hong, Wanjin

AU - Chakraborty, Sayan

PY - 2025/5/29

Y1 - 2025/5/29

N2 - Despite epidermal growth factor receptor (EGFR) is a pivotal oncogene for several cancers, including lung adenocarcinoma (LUAD), how it senses extracellular matrix (ECM) rigidity remain elusive in the context of the increasing role of tissue rigidity on various hallmarks of cancer development. Here it is shown that EGFR dictates tumorigenic agrin expression in lung cancer cell lines, genetically engineered EGFR-driven mouse models, and human specimens. Agrin expression confers substrate stiffness-dependent oncogenic attributes to EGFR-reliant cancer cells. Mechanistically, agrin mechanoactivates EGFR through epidermal growth factor (EGF)-dependent and independent modes, thereby sensitizing its activity toward localized cancer cell-ECM adherence and bulk rigidity by fostering interactions with integrin β1. Notably, a feed-forward loop linking agrin–EGFR rigidity response to YAP–TEAD mechanosensing is essential for tumorigenesis. Together, the combined inhibition of EGFR–YAP/TEAD may offer a strategy to reduce lung tumorigenesis by disrupting agrin-EGFR mechanotransduction, uncovering a therapeutic vulnerability for EGFR-addicted lung cancers.

AB - Despite epidermal growth factor receptor (EGFR) is a pivotal oncogene for several cancers, including lung adenocarcinoma (LUAD), how it senses extracellular matrix (ECM) rigidity remain elusive in the context of the increasing role of tissue rigidity on various hallmarks of cancer development. Here it is shown that EGFR dictates tumorigenic agrin expression in lung cancer cell lines, genetically engineered EGFR-driven mouse models, and human specimens. Agrin expression confers substrate stiffness-dependent oncogenic attributes to EGFR-reliant cancer cells. Mechanistically, agrin mechanoactivates EGFR through epidermal growth factor (EGF)-dependent and independent modes, thereby sensitizing its activity toward localized cancer cell-ECM adherence and bulk rigidity by fostering interactions with integrin β1. Notably, a feed-forward loop linking agrin–EGFR rigidity response to YAP–TEAD mechanosensing is essential for tumorigenesis. Together, the combined inhibition of EGFR–YAP/TEAD may offer a strategy to reduce lung tumorigenesis by disrupting agrin-EGFR mechanotransduction, uncovering a therapeutic vulnerability for EGFR-addicted lung cancers.

KW - EGFR, extracellular matrix

KW - YAP/TAZ

KW - agrin

KW - hippo pathway

KW - lung cancer

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U2 - 10.1002/advs.202413443

DO - 10.1002/advs.202413443

M3 - Article

C2 - 40165020

AN - SCOPUS:105001865548

SN - 2198-3844

VL - 12

JO - Advanced Science

JF - Advanced Science

IS - 20

M1 - 2413443

ER -

An Agrin–YAP/TAZ Rigidity Sensing Module Drives EGFR-Addicted Lung Tumorigenesis

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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